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Many studies suggest a significant association between individual essential trace elements (ETEs) and cognitive impairment in older adults, but evidence of the synchronized effect of multiple ETEs on cognitive function is lacking. We investigated the association between multiple ETEs, cognitive impairment with no dementia (CIND), and executive function in older Korean adults, using the Bayesian kernel machine regression (BKMR) model. Three hundred and thirty-six older adults were included as the study population and classified as the CIND and control groups. Blood manganese (Mn), copper (Cu), zinc (Zn), selenium (Se), and molybdenum (Mo) were measured as relevant ETEs. The frontal/executive tests included digit symbol coding (DSC), the Korean color word Stroop test (K-CWST), a controlled oral word association test (COWAT), and a trial-making test (TMT). Overall, the BKMR showed a negative association between multiple ETEs and the odds of CIND. Mn was designated as the most dominant element associated with the CIND (PIP = 0.6184), with a U-shaped relationship. Cu and Se levels were positively associated with the K-CWST percentiles (β = 31.78; 95% CI: 13.51, 50.06) and DSC percentiles (β = 25.10; 95% CI: 7.66, 42.53), respectively. Our results suggest that exposure to multiple ETEs may be linked to a protective mechanism against cognitive impairment in older adults. [ABSTRACT FROM AUTHOR]

This study compared the level of workplace violence experienced by personal healthcare workers in a district in Seoul, Republic of Korea, with those experienced by workers in office or service jobs. We matched 150 personal care workers with 150 office workers and 150 service workers using a propensity score. Workplace violence was categorized into psychological violence and physical violence. Of the surveyed personal care workers, 53.3% reported experiencing psychological violence, and 42.0% reported experiencing physical violence. After adjusting for self-reported work-related symptoms, personal care workers had significantly higher odds of experiencing psychological violence than office workers (OR = 5.01; 95% CI: 2.80–8.97) or service workers (OR = 7.54; 95% CI: 3.93–14.47). The adjusted odds for physical violence were also significantly higher for personal care workers compared with those for office workers (OR = 5.83; 95% CI: 2.96–11.50) and service workers (OR = 6.00; 95% CI: 2.88–12.49). In terms of specific types of workplace violence, personal care workers were 7–10 times more likely to experience unwanted sexual attention, sexual harassment, and physical violence than office or service workers. We found that personal care workers were more prone to workplace violence than office or service workers, with gender-based or physical violence being the most common types. Considering the negative impact of workplace violence on workers' well-being and health services, policy updates and interventions focusing on personal care workers are needed to reduce workplace violence, safeguard workers' rights, and establish a secure working environment. [ABSTRACT FROM AUTHOR]

Simple Summary: Early lung cancer detection is vital. Next-generation sequencing (NGS) enables cell-free DNA (cfDNA) liquid biopsy to detect genetic changes, such as copy number variations (CNVs). Recent machine learning (ML) analyses using cancer markers can identify anomalies, and developing methods based on ML for patient big data analysis is crucial for predicting cancer. We analyzed blood samples of 92 lung cancer patients and 80 healthy individuals, detecting significant differences in cancer markers, cfDNA concentrations, and CNV screening. Here, we used three algorithms of ML, such as Adaptive Boosting (AdaBoost), Multi-Layer Perceptron (MLP), and Logistic Regression (LR). ML analysis using cancer markers, cell-free DNA, and CNV individually exhibited relatively low discriminative power between cancer patients and healthy individuals. However, integrating multi-omics data into ML significantly improved accuracy, suggesting potential for precise cancer diagnosis. This study suggests the prospect of effectively distinguishing and diagnosing lung cancer from healthy individuals through blood-based ML analysis. Early detection of lung cancer is crucial for patient survival and treatment. Recent advancements in next-generation sequencing (NGS) analysis enable cell-free DNA (cfDNA) liquid biopsy to detect changes, like chromosomal rearrangements, somatic mutations, and copy number variations (CNVs), in cancer. Machine learning (ML) analysis using cancer markers is a highly promising tool for identifying patterns and anomalies in cancers, making the development of ML-based analysis methods essential. We collected blood samples from 92 lung cancer patients and 80 healthy individuals to analyze the distinction between them. The detection of lung cancer markers Cyfra21 and carcinoembryonic antigen (CEA) in blood revealed significant differences between patients and controls. We performed machine learning analysis to obtain AUC values via Adaptive Boosting (AdaBoost), Multi-Layer Perceptron (MLP), and Logistic Regression (LR) using cancer markers, cfDNA concentrations, and CNV screening. Furthermore, combining the analysis of all multi-omics data for ML showed higher AUC values compared with analyzing each element separately, suggesting the potential for a highly accurate diagnosis of cancer. Overall, our results from ML analysis using multi-omics data obtained from blood demonstrate a remarkable ability of the model to distinguish between lung cancer and healthy individuals, highlighting the potential for a diagnostic model against lung cancer. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the association between cognitive function and depressive symptoms in older couples while also examining the relationship between cognitive performance and the frequency of contact with adult children. A total of 96 couples volunteered for this study and provided their informed consent at enrollment. Participants completed a neuropsychological test battery consisting of five cognitive domains: attention, language and related functions, visuospatial functions, memory, and frontal/executive functions. Symptoms of depression were assessed using the short version of the Geriatric Depression Scale. The number of contacts with children was categorized into ≥1 per month and <1 per month. We found that the cognitive functions of husbands with depressed wives were significantly lower in the frontal/executive functions. In contrast, the wives' cognitive performance was not associated with the husbands' depressive symptoms. For couples who had contact with their adult children less than once a month, the odds of the husbands with lower cognitive performance were significantly higher, which was reflected in their scores in visuospatial and executive functions. Among older married couples, the cognitive functions of husbands may be influenced more by their wives' mental health and degree of contact with their adult children. This infers that wives and offspring may act as a buffer against the cognitive impairment of older married men. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to analyze the reliability and validity of a Korean version of the Nursing Student Attitudes and Knowledge Toward Lesbian, Gay, Bisexual, and Transgender Patients (K-NAKL) Scale, which measures health and heterosexual attitudes toward LGBT individuals. Background: Lesbian, gay, bisexual, and transgender (LGBT) individuals often face discrimination and a lack of care experience on the part of healthcare professionals. Introduction: In South Korea, the current knowledge and attitude measurement tools for medical staff regarding LGBT individuals are limited, as they only focus on homosexuality and do not account for different sexual orientations. Methods: The participants were 217 nursing college students aged 18–25. The item–total correlations method and Cronbach's alpha coefficient were used to analyze internal consistency reliability. Face validity, content validity, construct validity, and criterion validity testing were conducted to establish scale validity. We made sure to follow STROBE guidelines when carrying out this research. Results: The K-NAKL is a culturally appropriate instrument used to measure the attitudes and knowledge of Korean nursing students when it comes to LGBT health. Discussion: As LGBT health is increasingly gaining social interest, the nursing education curriculum needs to produce culturally competent graduates to meet the health needs of this vulnerable and marginalized population. The current study contributes to that goal. Conclusion: The K-NAKL is a valid and reliable tool with which to measure attitudes and knowledge regarding LGBT health among Korean nursing students. Implications for nursing: The K-NAKL can enable Korean nursing students to increase their knowledge and improve their attitudes when caring for the LGBT population. Implications for nursing policy and health policy: The study highlights the importance of incorporating LGBT-related health education into nursing curricula and developing inclusive policies to improve the quality of care and health outcomes for LGBT individuals. [ABSTRACT FROM AUTHOR]

The assessment of muscle mass and physical performance is essential for the diagnosis of sarcopenia. This study examined the validity of bioimpedance analysis (BIA) and a sensor-based short physical performance battery (SPPB) device for analyzing appendicular skeletal muscle mass (ASM) and physical performance. Forty-one older adults were measured for ASM and physical performance with two BIA devices (InBody770 vs. T-SCAN PLUS III) and two SPPB devices (manual mSPPB vs. sensor-based sSPPB). Validity statistics included the intraclass correlation coefficient (ICC) and Bland–Altman plots to examine the agreement of data from the BIA (InBody770 vs. T-SCAN PLUS III) and the SPPBs (mSPPB vs. sSPPB). There was a significant ICC for skeletal muscle mass between the T-SCAN PLUS III and InBody770 devices (ICC = 0.8822; p < 0.0001). The mSPPB and sSPPB values showed agreement across all components: 0.8654 for the total scores, 0.8879 for the walking speed, 0.8889 for the chair stand, and 0.6863 for the standing balance. No systemic bias was observed between the two methods for the BIA and SPPB devices. Measurements using the T-SCAN PLUS III and sSPPB seem to be highly correlated with the InBody770 and mSPPB devices in older adults and may be valid for assessing muscle mass and physical performance. [ABSTRACT FROM AUTHOR]

The dysregulation of lipid metabolism and alterations in the ratio of monounsaturated fatty acids (MUFAs) to saturated fatty acids (SFAs) have been implicated in cancer progression and stemness. Stearoyl-CoA desaturase 1 (SCD1), an enzyme involved in lipid desaturation, is crucial in regulating this ratio and has been identified as an important regulator of cancer cell survival and progression. SCD1 converts SFAs into MUFAs and is important for maintaining membrane fluidity, cellular signaling, and gene expression. Many malignancies, including cancer stem cells, have been reported to exhibit high expression of SCD1. Therefore, targeting SCD1 may provide a novel therapeutic strategy for cancer treatment. In addition, the involvement of SCD1 in cancer stem cells has been observed in various types of cancer. Some natural products have the potential to inhibit SCD1 expression/activity, thereby suppressing cancer cell survival and self-renewal activity. [ABSTRACT FROM AUTHOR]

We aimed to compare the prognosis of patients with close resection margins after breast-conserving surgery (BCS) with that of patients with negative margins and identified predictors of residual disease. A total of 542 patients with breast cancer who underwent BCS between 2003 and 2019 were selected and divided into the close margin (114 patients) and negative margin (428 patients) groups. The median follow-up period was 72 (interquartile range, 42–113) months. Most patients received radiation therapy (RTx) and systemic therapy according to their stage and molecular subtype. The 10-year locoregional recurrence-free survival rates of the close and negative margin groups were 88.2% and 95.5%, respectively (p = 0.001). Multivariable analysis showed that adjuvant RTx and margin status after definitive surgery were significantly associated with locoregional recurrence. Of the 57 patients who underwent re-excision, 34 (59.6%) had residual disease. Multivariable analysis revealed that a histological type of positive or close margins and multifocality were independent predictive factors for residual disease. Although the current guidelines suggest that no ink on tumor is an adequate margin after BCS, a close resection margin may be associated with locoregional failure. The treatment strategy for close resection margins after BCS should be based on individual clinicopathological features. [ABSTRACT FROM AUTHOR]

Patients with hypertension develop hemodynamic instability more frequently during anesthesia—particularly post-induction. Therefore, different monitoring methods may be required in patients with hypertension. Perfusion index—the ratio of the pulsatile blood flow to the non-pulsatile static blood flow in a patient's peripheral tissues, such as the fingers or ears—can show the hemodynamic status of the patient in a non-invasive way. Among the sites used for measuring the perfusion index, it is assumed that the ear is more reliable than the finger for hemodynamic monitoring, because proximity to the brain ensures appropriate perfusion. We hypothesized that the low value of preoperative ear PI could be a predictor of post-induction hypotension in patients with hypertension. Thirty patients with hypertension were enrolled. The perfusion index and pleth variability index were measured using the ear, finger, and blood pressure, and heart rate was recorded to monitor hypotension. After insertion of the supraglottic airway, 20 patients developed post-induction hypotension. Those who developed hypotension showed a significantly lower preoperative perfusion index of the ear. The preoperative perfusion index of the ear could predict post-induction hypotension in patients with hypertension. [ABSTRACT FROM AUTHOR]

The dose of propofol for pediatric sedation during radiologic tests has been proposed as an equation of 0.75 + 0.14 × age (months) + 45.82 × body surface area (m2) based on results in a previous study. We compared this equation and the conventional dosing strategy for sedation in children undergoing radiologic tests. An amount of 180 children scheduled for magnetic resonance imaging (MRI) were randomized to experimental and control groups. The initial induction dose of propofol calculated using the equation was administered in the experimental group. In the control group, children received 1 mg/kg of the initial induction dose of propofol. Then, 0.5 mg/kg of the additional dose was followed to induce sedation in both groups. When awake or moving, a rescue injection of 0.5 mg/kg propofol was given. The total induction dose was more significant in the experimental group. The number of injections for induction in the experimental group was lesser. The dose and number of rescue injections in the experimental group were significantly less. The equation for the induction dose of propofol in a previous study could achieve quick induction of sedation and prevent a rescue injection during sedation. However, caution is needed when using the equation. [ABSTRACT FROM AUTHOR]

In this study, a high-photoresponsivity self-powered deep ultraviolet (DUV) photodetector based on an Ag2O/β-Ga2O3 heterojunction was fabricated by depositing a p-type Ag2O thin film onto an n-type β-Ga2O3 layer. The device characteristics after post-annealing at temperatures ranging from 0 to 400 °C were investigated. Our DUV devices exhibited typical rectification characteristics. At a post-annealing temperature of 300 °C, the as-fabricated device had a low leakage current of 4.24 × 10−11 A, ideality factor of 2.08, and a barrier height of 1.12 eV. Moreover, a high photo-responsivity of 12.87 mA/W was obtained at a 100 μW/cm2 light intensity at a 254 nm wavelength at zero bias voltage, the detectivity was 2.70 × 1011 Jones, and the rise and fall time were 29.76, 46.73 ms, respectively. Based on these results, the Ag2O/β-Ga2O3 heterojunction photodetector operates without an externally applied voltage and has high responsivity, which will help in the performance improvement of ultraviolet sensing systems. [ABSTRACT FROM AUTHOR]

(1) Background: Several studies have reported that handgrip strength (HGS) may be a sign of lower cognitive performance. However, studies supporting an association between asymmetrical HGS and cognitive function are lacking. This study aimed to determine the association between asymmetrical HGS and cognitive performance among the elderly. (2) Methods: The study sample included 2729 individuals aged ≥60 years-old who participated in the 2011–2014 National Health and Nutrition Examination Survey. The cognitive tests consisted of the word learning and recall modules from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), Animal Fluency Test, and Digit Symbol Substitution Test (DSST). HGS was measured using a handgrip dynamometer, and asymmetrical HGS was used to calculate HGS. (3) Results: Of the 2729 participants, 53.0% were aged 60 to 69 years-old, and 47.0% were aged 70 years and older. All cognitive performance scores were significantly correlated with asymmetrical HGS in both age groups. After adjusting for confounders, there was a significant association between DSST and HGS asymmetry in both age groups. Contrastingly, a significant association was only observed for the relationship between the CERAD test and HGS asymmetry in the ≥70 year-old group. (4) Conclusions: We found that low cognitive function was associated with asymmetrical HGS in elderly participants in the United States. Thus, asymmetrical HGS may be an important predictor of cognitive deficits. However, further research is required to confirm our results and to establish possible mechanisms. [ABSTRACT FROM AUTHOR]

Previous studies have found an association between serum albumin levels and cognitive function. However, the results of this association are inconsistent, and the effect of Apolipoprotein E (APOE) on the association is less clear. Using retrospective cohort data (2008–2020), we investigated whether chronic serum albumin was associated with cognitive performance in older adults. We further assessed how the APOE genotype modifies its relevance. A total of 2396 Korean veterans and their families who were aged 65 years or older in 2008 and who had both data of serum albumin and cognitive performance (assessed by the Mini-Mental State Examination, MMSE) were included for the current study. The serum albumin levels were divided into four groups by quartiles: Group 1 (<4.0 g/dL), Group 2 (4.0–4.19 g/dL), Group 3 (4.2–4.49 g/dL), and Group 4 (≥4.5 g/dL). APOE ε4 carriers were defined as the presence of at least one ε4 allele (ε2/4, ε3/4, ε4/4). After adjusting for age, sex, and medical conditions, serum albumin levels (assessed by the median serum albumin levels during the study period) were significantly associated with increases in the median MMSE scores (beta = 3.30, p < 0.0001). Compared with the lowest median albumin category (Group 1), the beta coefficients for the median MMSE score were significantly and gradually increased in Group 2 (beta = 2.80, p < 0.0001), Group 3 (beta = 3.71, p < 0.0001), and Group 4 (beta = 4.01, p < 0.0001), respectively. In the analysis of repeated albumin measures, similar patterns were observed in cognitive function. All regression coefficients were greater in ε4 carriers than in non-carriers. Our findings suggested that sustained lower serum albumin levels were associated with lower MMSE scores. This observation may be modified by APOE polymorphisms. [ABSTRACT FROM AUTHOR]

Electromyogram (EMG) signals have been increasingly used for hand and finger gesture recognition. However, most studies have focused on the wrist and whole-hand gestures and not on individual finger (IF) gestures, which are considered more challenging. In this study, we develop EMG-based hand/finger gesture classifiers based on fixed electrode placement using machine learning methods. Ten healthy subjects performed ten hand/finger gestures, including seven IF gestures. EMG signals were measured from three channels, and six time-domain (TD) features were extracted from each channel. A total of 18 features was used to build personalized classifiers for ten gestures with an artificial neural network (ANN), a support vector machine (SVM), a random forest (RF), and a logistic regression (LR). The ANN, SVM, RF, and LR achieved mean accuracies of 0.940, 0.876, 0.831, and 0.539, respectively. One-way analyses of variance and F-tests showed that the ANN achieved the highest mean accuracy and the lowest inter-subject variance in the accuracy, respectively, suggesting that it was the least affected by individual variability in EMG signals. Using only TD features, we achieved a higher ratio of gestures to channels than other similar studies, suggesting that the proposed method can improve the system usability and reduce the computational burden. [ABSTRACT FROM AUTHOR]

(1) Background: Previous studies have suggested the association between lipid profiles and cognitive function in older adults. However, they generated inconsistent results. We aim to determine the relationship between lipid profiles and cognitive performance in older adults. (2) Methods: We used the 2011–2014 National Health and Nutrition Examination Survey. This study included 2215 participants who were aged more than 60 years old and free of coronary heart disease or stroke. Lipid profiles included total cholesterol (TC), low density lipid cholesterol (LDL), high density lipid cholesterol (HDL), and triglyceride (TG). Cognitive function was assessed using the digit symbol substitution test (DSST). (3) Results: Positive correlations of DSST were observed with TC (r = 0.111; p < 0.0001), HDL (r = 0.127; p < 0.0001), and LDL (r = 0.107; p = 0.0005). However, there was no significant relationship between TG and DSST. A one-unit increase in HDL was associated with an increase in DSST score (beta coefficient: 0.036; p = 0.018); but the association was not significant for LDL, TG, and TC. In the categorical analysis, the high HDL group had a higher DSST score than the low HDL group (beta = 3.113; p < 0.0001) and the low TG group was more likely to show a lower DSST score than the high TC group (beta = −1.837; p = 0.0461). However, LDL and TC showed no statistically significant associations. Moreover, HDL was only associated with a 0.701 times increased risk of cognitive impairment (95% CI = 0.523–0.938) in the logistic regression analysis. (4) Conclusions: Higher blood concentrations of HDL levels were positively associated with DSST scores in older adults. We suggest that the high levels of HDL may be a protective factor against cognitive impairment. [ABSTRACT FROM AUTHOR]

Saponarin{5-hydroxy-2-(4-hydroxyphenyl)-6-[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]-7-[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxychromen-4-one}, a flavone found in young green barley leaves, is known to possess antioxidant, antidiabetic, and hepatoprotective effects. In the present study, the anti-inflammatory, anti-allergic, and skin-protective effects of saponarin were investigated to evaluate its usefulness as a functional ingredient in cosmetics. In lipopolysaccharide-induced RAW264.7 (murine macrophage) cells, saponarin (80 μM) significantly inhibited cytokine expression, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, inducible nitric oxide synthase, and cyclooxygenase (COX)-2. Saponarin (80 μM) also inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) and p38 involved in the mitogen-activated protein kinase signaling pathway in RAW264.7 cells. Saponarin (40 μM) significantly inhibited β-hexosaminidase degranulation as well as the phosphorylation of signaling effectors (Syk, phospholipase Cγ1, ERK, JNK, and p38) and the expression of inflammatory mediators (tumor necrosis factor [TNF]-α, IL-4, IL-5, IL-6, IL-13, COX-2, and FcεRIα/γ) in DNP-IgE- and DNP-BSA-stimulated RBL-2H3 (rat basophilic leukemia) cells. In addition, saponarin (100 μM) significantly inhibited the expression of macrophage-derived chemokine, thymus and activation-regulated chemokine, IL-33, thymic stromal lymphopoietin, and the phosphorylation of signaling molecules (ERK, p38 and signal transducer and activator of transcription 1 [STAT1]) in TNF-α- and interferon (IFN)-γ-stimulated HaCaT (human immortalized keratinocyte) cells. Saponarin (100 μM) also significantly induced the expression of hyaluronan synthase-3, aquaporin 3, and cathelicidin antimicrobial peptide (LL-37) in HaCaT cells, which play an important role as skin barriers. Saponarin remarkably inhibited the essential factors involved in the inflammatory and allergic responses of RAW264.7, RBL-2H3, and HaCaT cells, and induced the expression of factors that function as physical and chemical skin barriers in HaCaT cells. Therefore, saponarin could potentially be used to prevent and relieve immune-related skin diseases, including atopic dermatitis. [ABSTRACT FROM AUTHOR]

O-linked-N-acetylglucosaminylation (O-GlcNAcylation) performed by O-GlcNAc transferase (OGT) is a nutrient-responsive post-translational modification (PTM) via the hexosamine biosynthetic pathway (HBP). Various transcription factors (TFs) are O-GlcNAcylated, affecting their activities and significantly contributing to cellular processes ranging from survival to cellular differentiation. Given the pleiotropic functions of O-GlcNAc modification, it has been studied in various fields; however, the role of O-GlcNAcylation during osteoclast differentiation remains to be explored. Kinetic transcriptome analysis during receptor activator of nuclear factor-kappaB (NF-κB) ligand (RANKL)-mediated osteoclast differentiation revealed that the nexus of major nutrient metabolism, HBP was critical for this process. We observed that the critical genes related to HBP activation, including Nagk, Gfpt1, and Ogt, were upregulated, while the global O-GlcNAcylation was increased concomitantly during osteoclast differentiation. The O-GlcNAcylation inhibition by the small-molecule inhibitor OSMI-1 reduced osteoclast differentiation in vitro and in vivo by disrupting the translocation of NF-κB p65 and nuclear factor of activated T cells c1 (NFATc1) into the nucleus by controlling their PTM O-GlcNAcylation. Furthermore, OSMI-1 had a synergistic effect with bone target therapy on osteoclastogenesis. Lastly, knocking down Ogt with shRNA (shOgt) mimicked OSMI-1's effect on osteoclastogenesis. Targeting O-GlcNAcylation during osteoclast differentiation may be a valuable therapeutic approach for osteoclast-activated bone diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the most common carcinoma and the leading cause of cancer-related death among women worldwide. Many kinases play important roles in the tumorigenesis of various cancers. IκBα phosphorylation is important for the regulation of NF-κB activity and is linked to the regulation of tumorigenesis. However, the kinase signaling network regulating IκBα phosphorylation in the context of cancer is not well understood. Herein, we report that RSK3 (RPS6KA2) is a novel binding partner of IκBα. RSK3 induces IκBα phosphorylation and NF-κB activation. Further, a chemical screening approach identified an inhibitor of RSK3/IκBα binding that impairs RSK3-mediated IκBα phosphorylation and decreases breast cancer cell survival, proliferation, and migration. Multiple cancer-related biological processes are mediated by protein-protein interactions (PPIs). Through interactions with a variety of factors, members of the ribosomal S6 kinase (RSK) family play roles in cell cycle progression and cell proliferation. In particular, RSK3 contributes to cancer viability, but the underlying mechanisms remain unknown. We performed a kinase library screen to find IκBα PPI binding partners and identified RSK3 as a novel IκBα binding partner using a cell-based distribution assay. In addition, we discovered a new PPI inhibitor using mammalian two-hybrid (MTH) analysis. We assessed the antitumor effects of the new inhibitor using cell proliferation and colony formation assays and monitored the rate of cell death by FACS apoptosis assay. IκBα is phosphorylated by the active form of the RSK3 kinase. A small-molecule inhibitor that targets the RSK3/IκBα complex exhibited antitumor activity in breast cancer cells and increased their rate of apoptosis. RSK3 phosphorylation and RSK3/IκBα complex formation might be functionally important in breast tumorigenesis. The RSK3/IκBα-specific binding inhibitor identified in this study represents a lead compound for the development of new anticancer drugs. [ABSTRACT FROM AUTHOR]

Therapeutic options for coronaviruses remain limited. To address this unmet medical need, we screened 5406 compounds, including United States Food and Drug Administration (FDA)-approved drugs and bioactives, for activity against a South Korean Middle East respiratory syndrome coronavirus (MERS-CoV) clinical isolate. Among 221 identified hits, 54 had therapeutic indexes (TI) greater than 6, representing effective drugs. The time-of-addition studies with selected drugs demonstrated eight and four FDA-approved drugs which acted on the early and late stages of the viral life cycle, respectively. Confirmed hits included several cardiotonic agents (TI > 100), atovaquone, an anti-malarial (TI > 34), and ciclesonide, an inhalable corticosteroid (TI > 6). Furthermore, utilizing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we tested combinations of remdesivir with selected drugs in Vero-E6 and Calu-3 cells, in lung organoids, and identified ciclesonide, nelfinavir, and camostat to be at least additive in vitro. Our results identify potential therapeutic options for MERS-CoV infections, and provide a basis to treat coronavirus disease 2019 (COVID-19) and other coronavirus-related illnesses. [ABSTRACT FROM AUTHOR]

Simple Summary: Local invasion and distal metastasis are the main causes of cancer-related death and the poor prognosis of patients with aerodigestive tract cancers. Therefore, understanding the biology of invasion and metastasis is important for the development of effective therapeutic strategies. The present study shows that insulin-like growth factor binding protein-3 (IGFBP-3) inhibits the migration and invasion of non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) cells in vitro and the development of metastasized tumors in vivo. Mechanistic studies suggest vimentin as a cellular target for the antimetastatic effect of IGFBP-3. These results contribute to a better understanding on the regulation of metastasis of cancer cells, providing the rationale to utilize IGFBP-3 as an effective therapeutic strategy targeting migration and metastasis of aerodigestive tract cancers. The proapoptotic, antiangiogenic, and antimetastatic activities of insulin-like growth factor binding protein-3 (IGFBP-3) through IGF-dependent or -independent mechanisms have been suggested in various types of human cancers. However, a mechanistic explanation of and downstream targets involved in the antimetastatic effect of IGFBP-3 is still lacking. In this study, by applying various in vitro and in vivo models, we show that IGFBP-3 suppresses migration and invasion of human head and neck squamous carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) cells. Silencing IGFBP-3 expression elevated the migration and invasion of NSCLC and HNSCC cells in vitro and their local invasion and metastasis in vivo, whereas overexpression of IGFBP-3 decreased such prometastatic changes. Local invasion of 4-nitroquinoline-1-oxide (4-NQO)-induced HNSCC tumors was consistently significantly potentiated in Igfbp3 knockout mice compared with that in wild-type mice. Mechanistically, IGFBP-3 disrupted the protein stability of vimentin via direct binding and promoting its association with the E3 ligase FBXL14, causing proteasomal degradation. The C-terminal domain of IGFBP-3 and the head domain of vimentin are essential for their interaction. These results provide a molecular framework for IGFBP-3′s IGF-independent antimetastatic and antitumor activities. [ABSTRACT FROM AUTHOR]

Slow-cycling cancer cells (SCCs) with a quiescence-like phenotype are believed to perpetrate cancer relapse and progression. However, the mechanisms that mediate SCC-derived tumor recurrence are poorly understood. Here, we investigated the mechanisms underlying cancer recurrence after chemotherapy, focusing on the interplay between SCCs and the tumor microenvironment. We established a preclinical model of SCCs by exposing non-small-cell lung cancer (NSCLC) cells to either the proliferation-dependent dye carboxyfluorescein diacetate succinimidyl ester (CFSE) or chemotherapeutic drugs. An RNA sequencing analysis revealed that the established SCCs exhibited the upregulation of a group of genes, especially epidermal growth factor (EGF). Increases in the number of vascular endothelial growth factor receptor (VEGFR)-positive vascular endothelial cells and epidermal growth factor receptor (EGFR) activation were found in NSCLC cell line- and patient-derived xenograft tumors that progressed upon chemotherapy. EGFR tyrosine kinase inhibitors effectively suppressed the migration and tube formation of vascular endothelial cells. Furthermore, activating transcription factor 6 (ATF6) induced the upregulation of EGF, and its antagonism effectively suppressed these SCC-mediated events and inhibited tumor recurrence after chemotherapy. These results suggest that the ATF6-EGF signaling axis in SCCs functions to trigger the angiogenesis switch in residual tumors after chemotherapy and is thus a driving force for the switch from SCCs to actively cycling cancer cells, leading to tumor recurrence. [ABSTRACT FROM AUTHOR]

Apigenin (4′,5,7-trihydroxyflavone, flavonoid) is a phenolic compound that is known to reduce the risk of chronic disease owing to its low toxicity. The first study on apigenin analyzed its effect on histamine release in the 1950s. Since then, anti-mutation and antitumor properties of apigenin have been widely reported. In the present study, we evaluated the apigenin-mediated amelioration of skin disease and investigated its applicability as a functional ingredient, especially in cosmetics. The effect of apigenin on RAW264.7 (murine macrophage), RBL-2H3 (rat basophilic leukemia), and HaCaT (human immortalized keratinocyte) cells were analyzed. Apigenin (100 μM) significantly inhibited nitric oxide (NO) production, cytokine expression (interleukin (IL)-1β, IL6, cyclooxygenase (COX)-2, and inducible nitric oxide synthase [iNOS]), and phosphorylation of mitogen-activated protein kinase (MAPK) signal molecules, including extracellular signal-regulated kinase (ERK) and c-Jun N-terminal protein kinase (JNK) in RAW264.7 cells. Apigenin (30 μM) also inhibited the phosphorylation of signaling molecules (Lyn, Syk, phospholipase Cγ1, ERK, and JNK) and the expression of high-affinity IgE receptor FcεRIα and cytokines (tumor necrosis factor (TNF)-α, IL-4, IL-5, IL-6, IL-13, and COX-2) that are known to induce inflammation and allergic responses in RBL-2H3 cells. Further, apigenin (20 μM) significantly induced the expression of filaggrin, loricrin, aquaporin-3, hyaluronic acid, hyaluronic acid synthase (HAS)-1, HAS-2, and HAS-3 in HaCaT cells that are the main components of the physical barrier of the skin. Moreover, it promoted the expression of human β-defensin (HBD)-1, HBD-2, HBD-3, and cathelicidin (LL-37) in HaCaT cells. These antimicrobial peptides are known to play an important role in the skin as chemical barriers. Apigenin significantly suppressed the inflammatory and allergic responses of RAW264.7 and RBL cells, respectively, and would, therefore, serve as a potential prophylactic and therapeutic agent for immune-related diseases. Apigenin could also be used to improve the functions of the physical and chemical skin barriers and to alleviate psoriasis, acne, and atopic dermatitis. [ABSTRACT FROM AUTHOR]

The relationship between caffeine and insulin resistance (IR) has been assessed only in terms of caffeine intake, and the association between caffeine and beta cell function (BCF) remains unclear. This study examines the association between urinary caffeine and its metabolites, IR, and BCF in nondiabetic, noninstitutionalized US adults in order to account for the inter-individual differences in caffeine metabolism. Data on urinary caffeine and its metabolites, IR and BCF from adults aged 20 years and older who participated in the 2009–2010 and 2011–2012 National Health and Nutrition Examination Surveys were analyzed (n for caffeine = 994). IR and BCF were assessed using homeostatic model assessment (HOMA) and urinary caffeine and its metabolites were measured using high-performance liquid chromatography-electrospray ionization-tandem quadrupole mass spectrometry. After adjusting for all covariates, increases in urinary 1,3-DMU, 1,7-DMU, 1,3,7-TMU, theophylline, paraxanthine, caffeine, and AAMU were significantly associated with increased HOMA-IR and HOMA-β (HOMA of insulin resistance and beta cell function). Compared with individuals in the lowest quartile of urinary 1,3-DMU, 1,7-DMU, 1,3,7-TMU, theophylline, paraxanthine, caffeine, and AAMU, the regression coefficients for HOMA-IR and HOMA-β were significantly higher among those in the highest quartile. After stratification by prediabetes status, HOMA-IR and HOMA-β showed significant positive associations with urinary caffeine and its metabolites among subjects with normal fasting plasma glucose levels. Our cross-sectional study showed that caffeine and its metabolites were positively related to IR and BCF. [ABSTRACT FROM AUTHOR]

Metabolic rewiring to utilize aerobic glycolysis is a hallmark of cancer. However, recent findings suggest the role of mitochondria in energy generation in cancer cells and the metabolic switch to oxidative phosphorylation (OXPHOS) in response to the blockade of glycolysis. We previously demonstrated that the antitumor effect of gracillin occurs through the inhibition of mitochondrial complex II-mediated energy production. Here, we investigated the potential of gracillin as an anticancer agent targeting both glycolysis and OXPHOS in breast and lung cancer cells. Along with the reduction in adenosine triphosphate (ATP) production, gracillin markedly suppresses the production of several glycolysis-associated metabolites. A docking analysis and enzyme assay suggested phosphoglycerate kinase 1 (PGK1) is a potential target for the antiglycolytic effect of gracillin. Gracillin reduced the viability and colony formation ability of breast cancer cells by inducing apoptosis. Gracillin displayed efficacious antitumor effects in mice bearing breast cancer cell line or breast cancer patient-derived tumor xenografts with no overt changes in body weight. An analysis of publicly available datasets further suggested that PGK1 expression is associated with metastasis status and poor prognosis in patients with breast cancer. These results suggest that gracillin is a natural anticancer agent that inhibits both glycolysis and mitochondria-mediated bioenergetics. [ABSTRACT FROM AUTHOR]

Middle East respiratory syndrome coronavirus (MERS-CoV) induces severe aggravating respiratory failure in infected patients, frequently resulting in mechanical ventilation. As limited therapeutic antibody is accumulated in lung tissue following systemic administration, inhalation is newly recognized as an alternative, possibly better, route of therapeutic antibody for pulmonary diseases. The nebulization process, however, generates diverse physiological stresses, and thus, the therapeutic antibody must be resistant to these stresses, remain stable, and form minimal aggregates. We first isolated a MERS-CoV neutralizing antibody that is reactive to the receptor-binding domain (RBD) of spike (S) glycoprotein. To increase stability, we introduced mutations into the complementarity-determining regions (CDRs) of the antibody. In the HCDRs (excluding HCDR3) in this clone, two hydrophobic residues were replaced with Glu, two residues were replaced with Asp, and four residues were replaced with positively charged amino acids. In LCDRs, only two Leu residues were replaced with Val. These modifications successfully generated a clone with significantly greater stability and equivalent reactivity and neutralizing activity following nebulization compared to the original clone. In summary, we generated a MERS-CoV neutralizing human antibody that is reactive to recombinant MERS-CoV S RBD protein for delivery via a pulmonary route by introducing stabilizing mutations into five CDRs. [ABSTRACT FROM AUTHOR]